Cellular proliferative orders such as cancer are among the most common causes of death in developed countries. For diseases for which treatments exist, such as cancer, despite continuing advances, the existing treatments have undesirable side effects and limited efficacy. Identifying new effective drugs for cellular proliferative disorders, including cancer, is a continuing focus of medical research.
Mammalian Polo Kinases: There are five mammalian Polo kinases, termed Polo-like kinase (Plk) 1, 2, 3, 4 and 5. Of these, Plk1 is the most extensively characterized member and is linked to cell cycle control in the G2/M phases. The protein is relevant to cancer biologists due to its over-expression in a variety of human tumor types, whereby over-expression is linked to poor prognosis.
Plk2, or Snk has been identified as an immediate-early gene product. Studies have shown that inhibiting the expression of this gene by siRNA leads to mitotic catastrophe in paclitaxel-treated cells. Furthermore, Plk2 null mutant embryos and embryo fibroblasts display defects in cell cycle progression with respect to decreased proliferation and delayed entry into S phase, respectively, demonstrating a role for this protein in cell cycle regulation. PLK-2 plays an important role in cell cycle control through the specific phosphorylation of centrosome-associated substrates. Specifically, PLK-2 regulates centriole duplication that occurs at the G1/S border and is coordinately regulated by CDK2/cyclin E complexes, CDK2/cyclin A complexes, and PLK4.
Inhibitors of polo-like kinases tend to affect both Plk1 and Plk2, and Plk1 inhibitors have been shown to induce severe myelo-suppression in human subjects. Thus, an antiproliferative agent that is selective for inhibiting Plk2, without affecting PLk1, would be desirable.